Certain phenylalkylbenzyl carbinols are known to possess analgesic activity. Specifically, the .alpha.,.beta.-(d,1)-(4-dimethylamino-1,2-diphenyl-3-methyl-2-butanol) possesses marked analgesic activity. It has been demonstrated that the analgesic activity resides in the dextrorotatory (.alpha.-d) enantiomer. Canadian Patent 1060013 (Gianantonio et al) discloses two methods to prepare the dextrorotatory (.alpha.-d) enantiomer of the desired phenylalkylbenzyl carbinols. Gianantonio et al disclose the following two methods: ##STR1##
According to method (a) the racemic 1-phenyl-2-lower alkyl-3-substituted amino-1-propanone undergoes a Grignard reaction leading predominantly, about 85 to 90%, to the .alpha.-diastereoisomer. The mixture is separated into the .alpha. and .beta. components by fractional crystallization from aqueous ethanol, the diastereoisomer .alpha. being the less soluble component. In accordance with the usual practice the .alpha.-diastereoisomer is then resolved into the d and 1 enantiomers by reaction with an optically active acid to form two diastereoisomeric salts which are in turn readily separable by fractional crystallization. The .alpha.-d enantiomer when esterified with an alkyl anhydride, such as propionic anhydride, does not change its configuration.
According to method (b), the .alpha. and .beta. components of 1,2-diphenyl-2-hydroxy-3-lower alkyl-4-substituted-aminobutane are obtained by regiospecific opening of the epoxide formed by reaction of (d,1)-1-phenyl-2-lower alkyl-3-substituted amnio-1-propanone and dimethyl sulfoxonium methylide. The separation of the .alpha. and .beta. components, the resolution of the a fraction and the esterification of the .alpha.-d-enantiomer are carried out following the above procedures.
As can be seen from the above schemes, the .beta.-(d,1)-diastereoisomers and substantial quantities of the .alpha.-1-isomer are undesirable by-products whose formation is responsible for the low overall yields of analgesically active substance. The yields of both processes (a) and (b) above range from about 40 to 45%.
The stereoselective .alpha.-alkylation of the .beta.-hydroxyester is disclosed by G. Frater, Tetrahedron Letters, 22, 425. The .beta.-hydroxyester is reacted with 2 equivalents of lithium diamine to from the dianion. The dianion is alkylated with an alkylhalide to form the .alpha.-alkyl of the .beta.-hydroxyester. The alkylation of .beta.-hydroxyamide is not disclosed, nor the use of such intermediate to prepare an .alpha.-d-phenylalkylbenzyl carbinol.
The above methods fail to disclose the present method of preparing an .alpha.-d-phenylalkylbenzyl carbinol.